MOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, China.
Department of Hepatobiliary, and Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
EMBO Rep. 2023 Mar 6;24(3):e55762. doi: 10.15252/embr.202255762. Epub 2023 Jan 4.
N -Methyladenosine (m A) is an important RNA modification catalyzed by methyltransferase-like 3 (METTL3) and METTL14. m A homeostasis mediated by the methyltransferase (MTase) complex plays key roles in various biological processes. However, the mechanism underlying METTL14 protein stability and its role in m A homeostasis remain elusive. Here, we show that METTL14 stability is regulated by the competitive interaction of METTL3 with the E3 ligase STUB1. STUB1 directly interacts with METTL14 to mediate its ubiquitination at lysine residues K148, K156, and K162 for subsequent degradation, resulting in a significant decrease in total m A levels. The amino acid regions 450-454 and 464-480 of METTL3 are essential to promote METTL14 stabilization. Changes in STUB1 expression affect METTL14 protein levels, m A modification and tumorigenesis. Collectively, our findings uncover an ubiquitination mechanism controlling METTL14 protein levels to fine-tune m A homeostasis. Finally, we present evidence that modulating STUB1 expression to degrade METTL14 could represent a promising therapeutic strategy against cancer.
N6-甲基腺苷（m6A）是一种由甲基转移酶样蛋白 3（METTL3）和 METTL14 催化的重要 RNA 修饰。甲基转移酶（MTase）复合物介导的 m6A 动态平衡在各种生物过程中发挥着关键作用。然而，METTL14 蛋白稳定性的机制及其在 m6A 动态平衡中的作用仍不清楚。在这里，我们表明，METTL14 的稳定性受到 METTL3 与 E3 连接酶 STUB1 的竞争性相互作用的调节。STUB1 直接与 METTL14 相互作用，介导其赖氨酸残基 K148、K156 和 K162 的泛素化，随后进行降解，导致总 m6A 水平显著降低。METTL3 的氨基酸区域 450-454 和 464-480 对于促进 METTL14 稳定至关重要。STUB1 表达的变化会影响 METTL14 蛋白水平、m6A 修饰和肿瘤发生。总之，我们的研究结果揭示了一种控制 METTL14 蛋白水平的泛素化机制，以精细调节 m6A 动态平衡。最后，我们提出了一种有前途的治疗策略，即通过调节 STUB1 表达来降解 METTL14 以对抗癌症。
